PROJECT SUMMARY/ABSTRACT Our goal is to characterize the genetic and environmental influences on normal aging-related changes in neuroanatomic, neurophysiologic and neurocognitive indices. Using data collected in large, randomly selected pedigrees from the Genetics of Brain Structure and Function (GOBS) study, we previously documented genotype age (GA) interactions influencing neurocognitive decline and reduced cortical thickness within medial temporal and parietal cortices. While these findings implicate genetic factors in brain aging, they are based on cross-sectional data and lack direct evaluation of intra-individual aging. More powerful methods for the detection of genetic and environmental influences of healthy aging require longitudinal data. Thus, we propose a pedigree-based, mixed longitudinal study to re-phenotype the oldest 700 GOBS individuals ~10 years after their initial assessment. A 10-year interval is ideal for measuring age-related cognitive, neuroanatomic and neurophysiological declines as practice effects and other phasic alterations are minimized. Individuals in the GOBS cohort have intensive genetic and phenotypic characterization, including whole genome sequencing (WGS), comprehensive neurocognitive assessment, structural and functional brain imaging and blood-based environmental indices. Our specific aims are to (1) document 10-year neurocognitive and neuroimaging declines in 700 non-demented GOBS participants (current age 69.05+8.4 [57-102]); (2) employ our GA approach to establish longitudinal brain aging phenotypes; (3) identify sequence variation in candidate genes/pathways previously associated with normal or pathological aging that influencing brain aging phenotypes and replicate these findings in archival samples; and (4) apply a novel statistical approach to maximize systematic environmental signals to identify environmental influences on brain aging phenotypes. Delineating the genetic and environmental architecture of age-related neurocognitive and neuroimaging changes will offer important biological insights which in turn could provide strategies for increasing the numbers of Americans who successfully age. Dr. David Glahn, Yale University, and Dr. John Blangero, University of Texas Rio Grande Valley Medical School, are co-principal investigators on this application and Dr. Rene Olvera, University of Texas Health Science Center San Antonio, will lead a subcontract. Given the wealth of phenotypic, environmental and genotypic data already available in this cohort, the proposed study represents a readily available, cost- effective, and powerful resource for elucidating mechanisms of brain aging.